He played college baseball for the Dartmouth Big Green under head coach Bob Whalen. In his junior year, Hendricks pitched to a 6–3 win–loss record and a 2.47 earned run average with 70 strikeouts in 62 innings pitched. In 2010, he played collegiate summer baseball with the Brewster Whitecaps of the Cape Cod Baseball League.

Hendricks grew up in San Juan Capistrano, California. His father, John, is a golf pro; his mother, Ann Marie, is a medical-management consultant. He received his bachelor’s degree in economics from Dartmouth College in December 2013, after completing his coursework in the winter of 2012 and fall of 2013. Hendricks is nicknamed “The Professor” by his teammates and fans. The nickname is not only a reference to Hendricks’ Ivy League education, but also an homage to Greg Maddux, who also sported the same nickname. Hendricks chose “Hendo” as his nickname for the Players Weekend during the 2017 season.

After the trade of Jeff Samardzija and Jason Hammel to the Oakland Athletics on July 4, 2014, Hendricks made his Major League Baseball debut with the Chicago Cubs on July 10, 2014 against the Cincinnati Reds at Great American Ballpark. He earned his first win in front of a home crowd against the San Diego Padres on July 22, 2014. Hendricks was named the National League Rookie of the Month of August. Hendricks finished his rookie season with a 7–2 win-loss record and a 2.46 ERA. Hendricks tied for seventh place with Travis d’Arnaud and Jeurys Familia in the NL Rookie of the Year Award voting.

His record was 8–7 with 180 innings pitched and he had an ERA of 3.95. His 17 no decisions were the most among MLB starting pitchers in 2015. He was the starter for game two of the 2015 National League Division Series with St. Louis and game three in the 2015 National League Championship Series against the New York Mets.

On June 8, 2017, Hendricks was placed on the 10-day disabled list (transaction retroactive three days prior) due to middle finger tendon inflammation in his right hand.

Hendricks married longtime girlfriend Emma Cain in November 2017.

In 2018, he was 14–11 with a 3.44 ERA and led all major league pitchers in changeup percentage (30.7%). He was the losing pitcher in the NL Wild Card Game, giving up three straight hits and one run in the 13th inning against the Colorado Rockies.

On March 26, 2019, Hendricks and the Cubs agreed to a four-year contract extension through the 2023 season with a vesting option for the 2024 season. Hendricks picked up his first career Maddux with an 81-pitch victory over the Cardinals on May 3. Hendricks, who was already aware of the term, stated, “Lucky I got one. Every time I go out there, I’m trying to get early contact and get early outs. When it happens to go this way, you can say, ‘Look, I did it!'”

On July 24, 2020, Hendricks pitched a complete game shutout in the Cubs’ season opener versus the Brewers, only throwing 103 pitches with 3 hits allowed, 9 strikeouts, and no walks. It was the first Opening Day shutout by a Cubs pitcher since Bill Bonham in 1974, and the first Opening Day shutout in MLB since Clayton Kershaw in 2013.

In 2020 he was 6-5 with a 2.88 ERA. He led the NL in fewest walks per 9 IP (0.885), and in strikeout/walk ratio (8.000), and was 8th in losses.